On December 1, 2020, Parsolex and Syntegon Pharma Technology hosted a technical forum entitled “Solving Scale-Up and Technical Challenges in Batch and Continuous Pharmaceutical Production” in West Lafayette, IN, and online. This article contains excerpts from the forum as well as additional comments concerning the application of continuous manufacturing processes in the pharmaceutical industry.
What are the benefits of continuous manufacturing?
Stacy Pearce, PE, manager, manufacturing solutions, Parsolex:
The generally accepted benefit of continuous manufacturing is improved product quality; however, another benefit is improved efficiency. One of the main goals of any production process is to achieve lean manufacturing—minimizing waste while maximizing productivity. Given the high cost of many active pharmaceutical ingredients (APIs), the benefits of reducing unnecessary waste from a pharmaceutical process cannot be overstated. Batch-based processes are less efficient than continuous processes, owing to increased waste, longer production cycles, and increased intermediate inventory.
Where appropriate, a continuous process can eliminate problems encountered during scale up of batch processes, as continuous processes do not involve discrete scale-up steps, but rather a clear production time variable that can be changed according to product demand. This offers the opportunity for savings during product development.
Yield from continuous manufacturing is significantly better than from batch manufacturing, as continuous manufacturing integrates multiple processes into a single process with an overall yield and eliminates sublots. For example, when a batch-based tablet production process consists of four consecutive process steps (such as highshear granulation, drying, tableting, and coating) and each step produces a yield of 97 percent, the overall yield for this batch is 88 percent.
Production time is also significantly shorter for a continuous process, largely because it eliminates non-value-adding wait times between batch process stages (such as transfer, weighing, and calculation). In addition to the wait time between batch process stages, each stage requires manual product handling, which further increases production costs. A batch-based process is governed by the size of the equipment or container used during production, while a continuous process is governed by product flow rates. This allows for smaller equipment, which can reduce your manufacturing footprint. Continuous manufacturing also provides a means of getting closer to the factory of the future.
Fritz-Martin Scholz, product manager, Syntegon Pharma Technology:
While the benefits have not yet been fully achieved in the market, continuous manufacturing promises reduced development time and cost; reduced manufacturing cost; and continuous, inline quality verification, leading to improved quality assurance and, eventually, real time release (RTR).
Currently, however, continuous processes require more material and time for model development—process analytical testing (PAT) and residence time distribution (RTD)—qualification in R&D, and often also for production. By using compact, agile, fully automated equipment, continuous manufacturing promises flexible, one-step tablet production, with no intermediate storage and reduced floor space requirements and cost, but most systems currently on the market are complex, expensive, not agile, and difficult to clean. Inline quality verification with PAT tools can still be a challenge and requires intensive modeling for each product. Many continuous processes are sensitive and not robust, and generally, batch registration with release testing is still in place.
How might the testing strategy for a drug product differ for a continuous manufacturing process compared to a batch manufacturing process?
Dr. Marc Michaelis, head of pharma services, Syntegon Pharma Technology:
The FDA and the International Council for Harmonisation (ICH) have provided guidance for developing and validating effective test methods based on a risk-based approach. The risk and the complexity of the manufacturing process define the testing strategy. A continuous manufacturing system, especially with RTR and an increased number of critical quality attributes (CQA), requires greater effort to continuously monitor the process than a batch system. However, for Syntegon’s Xelum continuous manufacturing process, the test strategy is less complex and more comparable to a batch process.
Nathan Wade, PhD, MBA, senior managing chemist, analytical solutions, Parsolex:
The testing strategy for a drug product manufactured by a continuous process does not necessarily need to differ from the testing strategy for the same drug product manufactured by a batch process. However, the inherent application of PAT and finer process controls within a continuous process may allow for some laboratory-based test methods to be replaced with on-line or real-time analysis. On-line spectroscopic techniques may be equally effective as laboratory-based chromatographic and titration methods for the identification, assay, or water determination of the drug product.
The dissolution test for tablets and capsules is an arduous laboratory-based test method intended to predict the release rate of the drug under biorelevant conditions and serve as a quality control for the manufacturer. Potentially, even the traditional dissolution test could be replaced with real-time analysis. For example, control and on-line characterization of the particle size of the active component, at-line determination of tablet hardness, and on-line content uniformity determination for the drug product could provide product specifications that are as clinically relevant as the dissolution test. The concept that all product release tests could be performed in real time for a given drug product is intriguing from both a quality and cost benefit perspective.
In practice, however, whether implementing a continuous or batch process, totally replacing laboratory-based methods with on-line or real-time analysis is a tough hill to climb. A number of product quality attributes are not conducive to on-line analysis, such as related impurities content, elemental impurities content, and microbiological content. Further, the same laboratory-based methods that one might hope to avoid in product release testing are still required for product stability testing.
What analytical challenges might exist for a continuous manufacturing process as compared to a batch manufacturing process?
Wade:
Implementing PAT into a continuous manufacturing process requires different technology and skills than the conventional off-line laboratory-based test methods required for a batch process. Spectroscopic tools, which are the most commonly used techniques to obtain data from PAT measurements, require significant amounts of data processing, data modeling, and statistical treatment that are less common for off-line test methods.
Further, PAT tools often need to be custom fit to the continuous process equipment to ensure proper data acquisition and establish feedback control to the process. The analytical response and equipment operating conditions must remain synchronized, such that the analytical response for a specific time corresponds to the equipment parameters collected at that time, correcting for any lags in sampling and instrument measurements.
The sampling strategy for product release testing is another challenge that may differ for products manufactured using a continuous approach versus a batch approach. Whereas samples are physically removed at discrete stages of a batch for the purpose of in-process testing or final product release testing, sampling during a continuous process is defined by time and frequency using online tools. During the initial scaleup and validation of the continuous process, on-line detection methods may need to be verified by off-line laboratory test methods.
Michaelis:
Monitoring content uniformity over the complete continuous process with adequate time resolution is the most critical challenge, especially for products with low API concentrations or complex material properties. The traceability of typical fluctuations in the powder flow and the determination of RTD is requiring additional development effort. The analytical strategy must be set up following a risk-based approach to evaluate which risks might additionally occur compared to a classical batch process. Here, dosing plays an important role, as it differs significantly between batch and continuous manufacturing.
In a continuous setup, feeders must be refilled from time to time. During refill, the feeder’s weight signal cannot be used, which means that the loss-in-weight feeders are running “blind” in volumetric mode for about 10 percent of the overall processing time. While some systems use algorithms to compensate for these interruptions, volumetric dosing is still risky, especially for non-particle-engineered substances such as APIs at low feed rates. Algorithms cannot predict for all possible incidents, such as bearding, ratholing, lumps, vibration, or shocks. Regulatory bodies have also recognized this. As a result, redundant measurement systems such as spectrometers are needed to verify the dosing accuracy. An alternative dosing system such as the one used by the Xelum can eliminate this disadvantage.
What are the critical studies to develop a continuous process?
Michaelis:
Besides the design of experiments (DOE) studies, the development of suitable PAT and RTD models are critical, especially considering the increased material consumption. All inline testing methods must be validated, therefore test results determining whether a product portion needs to be released or rejected must be correlated to a respective amount of product. Syntegon’s Xelum process offers an advantage here because the system’s design doesn’t necessarily require RTD and PAT functions, yet it can integrate all inline tests applicable for continuous processing. Material traceability is simplified in the Xelum system, which precisely doses ingredients in mini packages, called X-keys, which can be traced throughout the production process.
Ammar Khawam, PhD, MBA managing scientist, development solutions, Parsolex:
A robust continuous process necessitates a clear understanding of the raw material properties and the performance of unit operations. For example, taking a fit-for-purpose approach to selecting raw materials and excipients is essential not only for achieving the critical product performance attributes, but also for identifying materials that will be suitable for operating a process over extended periods of time. For oral solid dosage (OSD) products, a particle engineering approach can be useful for such purpose, where material properties of the excipients and in-process materials are assessed during formulation design to understand the impact of properties such as particle size and distribution, flow behavior under different process stresses, and bulk and tapped densities.
Additionally, generating both in-specification and out-of-specification (OOS) product should inform robust process conditions. Again, using OSD products as an example, these studies would include assessing the performance of unit operations, such as loss-in-weight feeders, that are critical to achieving dose uniformity and potentially using raw materials with varying physical attributes. Developing an understanding of the overall process cycle time and how the machine speed for each stage of a continuous process affects critical product performance attributes are also important. To this end, a carefully planned and executed DOE to determine the cause-and-effect relationship between the factors affecting a process and product is indispensable.
How is quality assurance improved with continuous manufacturing processes?
Tony Stuckwisch, RPh, director, quality assurance, Parsolex:
Quality indicating data (such as yield and concentration) is available in real time in a continuous process rather than only at the end of a batch. Feedback loops and properly designed control systems minimize the impact of small disturbances. Continuous processes require less dependence on manual intervention and manual product handling, reducing the risk of errors. The risk of OOS material going undetected and not being rejected is reduced. To successfully operate a continuous process, a high degree of process understanding is essential.
Michaelis:
Quality by Design (QbD) and the use of automated product development tools, such as automated DOE, allow for more information in development and will help robust processing in production. Also, the avoidance of scale up will increase quality in production and reduce risks. In the Xelum process, each X-key contains all manufacturing data, such as raw material data, CQAs, CPPs, and sensor data, allowing for fingerprint comparison between X-keys to keep the process within specification.
What are the challenges with equipment cleaning or cleaning validation and product changeover for continuous manufacturing compared to batch manufacturing?
Pearce:
The primary challenges for equipment cleaning and changeover for continuous process equipment are time and complexity. Continuous manufacturing processes require more complex equipment than conventional batch equipment. To minimize cleaning time, continuous process equipment should be designed for cleanability (free-draining, with no dead legs) and should leverage clean-in-place (CIP) systems where appropriate. Cleanable equipment with CIP results in more reproducible cleaning compared to manual cleaning by a trained operator. Developing appropriate CIP processes for any new product takes time and effort but having a reproducible cleaning method helps facilitate cleaning validation efforts.
Scholz:
Syntegon does not consider any difference in the cleanability requirements between batch and continuous processes. Early machines developed for continuous manufacturing did not consider cleanability in their design, resulting in unacceptably long cleaning times and extremely complex cleaning validation and eliminating the cost-reduction benefits of continuous processing. The new generation of continuous systems, such as Xelum, incorporate automatic cleaning into their design, fulfilling the same cleaning requirements as batch equipment in addition to containment requirements.
Do you anticipate that processes will be conceived only following a continuous approach, or will new product development always start with a batch strategy and convert established batch processes to continuous?
David Engers, PhD, director, Parsolex:
One advantage of continuous processing as stated by the FDA Center for Drug Evaluation and Research (CDER) is drug production tailored to meet the needs of precision medicine. While this ultimate goal to manufacture and release lifesaving medicines at the point of patient use is not yet fully realized, continuous manufacturing is gaining more interest from industry sponsors, contract development and manufacturing organizations (CDMOs), and regulatory bodies for its ability to produce high-quality, safe, and effective pharmaceutical products.
Continuous pharmaceutical processes are by nature more efficient than conventional batch processes, and considerable advances are being made. Today, quantities of clinical trial materials (CTM) required to support first-in-human studies rarely justify adopting a continuous approach during early clinical development. Therefore, batch and continuous processes can be developed in parallel to help inform the decision for which strategy to adopt during late-stage clinical development and commercial manufacturing. For new chemical entities (NCEs) pursuing a new drug application (NDA), this decision commonly occurs after completing pivotal (Phase II) studies. For abbreviated new drug application (ANDA) products, continuous process development can be initiated at the start of product and process development.
As the pharmaceutical industry strives to achieve lean production and six sigma operational efficiency, learning from and applying the best practices of other industries where continuous processes are well established will likely allow continuous manufacturing strategies to be adopted earlier in the product development lifecycle.
Michaelis:
Syntegon will not advise a complete switch in R&D to continuous, as the current solutions on the market are not flexible enough to cover all requirements. A better strategy for both brand owners and CDMOs would be to have hybrid solutions that can serve both batch and continuous to keep all manufacturing strategies open. For instance, transferring from classic batch high-shear or fluid-bed granulation to continuous twin-screw granulation is difficult because these processes result in differences in end-product quality.
What are the technical and regulatory challenges with converting a legacy batch process to continuous?
Stuckwisch:
Among the technical challenges in converting a legacy batch process to continuous manufacturing is the need for advanced systems to maintain process control during the long run duration. Conversion difficulties include different technologies used for PAT than for in-process testing. Also, sample timing and location may be different. The process parameter design space is typically different for a continuous process than for a batch-based process. While other justifications, such as containment of highly potent materials, are possible, products with high volumes, high forecast variability due to launch or generic competition, and supply-chain risk often deliver the most return on investment from a batch-to-continuous conversion.
Michaelis:
The same rules apply for converting a legacy batch process to a continuous as converting from one batch process to another. Again, a risk-based approach is followed, evaluating all changes that might influence the product’s quality, safety, and efficacy. Changing the type of manufacturing process or even the formulation involves a high level of risk and might necessitate bioequivalence studies. We already know this from converting between batch processes such as from high-shear to fluid-bed granulation or vice versa.
Why are regulatory authorities in favor of continuous manufacturing strategies?
Michaelis:
Authorities are interested in an efficient, agile, flexible manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight, and the idea is that continuous manufacturing can fulfill these interests. Again, a big gap still exists between the promise of continuous manufacturing and the status of the technology today, but an increased focus on quality and test strategy, increased process knowhow, and more QbD will definitely help to reach the goal.
Stuckwisch:
Regulatory authorities see the benefits of the degree of process monitoring that is needed for continuous manufacturing, which helps maintain a state of validation and process control. The ability to monitor quality using leading rather than lagging indicators provides improved process control and quality assurance, decreasing the likelihood of batch loss or rejection and drug shortages.
Parsolex
West Lafayette, IN
765 464 8414
www.parsolexinc.com
Syntegon Pharma Technology
Minneapolis, MN
763 424 4700
www.syntegon.com